The rate of depression has been rising over the years. It affects 17.6 million Americans every year, robbing people of a fulfilling life with a cost of about $44 to $52.9 billion annually. It carries the risk of suicide with 30,000 to 35,000 deaths a year, a rate that resembles the death rate from leukemia.
The first treatments for severe mental disturbances became available in the 1930's, when extracts from the plant rauwolfia serpentina were used for the amelioration of psychotic symptoms. Major advances in the treatment of psychosis, however, did not come until 1950 with the discovery of chlorpromazine. The first generation of antidepressants did not become available until the 1950's, and included monoamine oxidase inhibitors and tricyclic antidepressants. While chlorpromazine was used early on in the treatment of depression, as tricyclic antidepressants became available the use of antipsychotic medications declined, and they were never widely used in the treatment of depression in the absence of psychotic symptoms. See also Raskin A. et al 1970, p.170: “There is a persistent belief that these drugs (antipsychotics) are not very effective in the treatment of depression”. In general, the use of antipsychotic drugs was reserved for use in patients having psychotic symptoms. It was generally accepted that antipsychotic drugs used alone could not treat major depressive disorder. In fact, it was thought that antipsychotic drugs, including some of the a typical antipsychotics, may even have depressogenic properties. (Harrow, M. et al 1994, Galdi J. 1983, Tollefson, G. D. et al 1998, Maguire, G. A. 2002, Cookson I. B. et al.)
In contrast to antidepressants, antipsychotics alone (including the a typical antipsychotic risperidone) were ineffective in the chronic mild stress (CMS) model (animal simulation of depression) (Papp, M. et al 1996; Papp, M. et al 2000). In sum, many studies showed that antipsychotics do not have significant antidepressant activity and, if anything, may cause a depressogenic effect.
Due to the severe side effect profiles of the traditional antipsychotic drugs, the risks of taking these drugs, in the absence of their specific indications (such as psychosis, severe agitation or anxiety) were believed to be unwarranted by the medical community. (Price, L. H. et al. 2001. p. 207.)
Such risks included side effects such as tardiv dyskinesia (TD), a potentially irreversible effect involving involuntary movement or other dyskinetic movements, or the rare but potentially fatal neuroleptic malignant syndrome (NMS). Many states (e.g. MN) require written consent forms from patients prior to starting an antipsychotic medication in inpatient psychiatric settings, and some outpatient clinics have also adapted that policy.
Early reports compared the antidepressant efficacy of two older/traditional groups of medications, the tricyclics (TCA) and traditional antipsychotics, or their use in combination, (Robertson, M., et al. 1982; Hollister, 1967). This review by Robertson (Robertson, M. M. et al. 1982) was based mostly on studies with mixed-anxiety depressive states, now more appropriately called as depression with anxiety as a comorbid disorder (Zimmerman, 2002). The combination use had been reserved for psychotic depression. A later review summarized the opinion, that “while a ‘true’ antidepressant effect has been demonstrated for the tricyclic antidepressants, similar effects appear doubtful for the antipsychotic drugs.” (Nelson, J. C., 1987).
The combination use of these medications to treat non-treatment resistant, and non-psychotic depression was never recommended. A book chapter reviewing this topic from year 2001 makes the point that “the risk/benefit ratio in refractory patients lacking such features [as near-psychotic rumination or marked psychomotor agitation] generally does not favor [antipsychotic augmentation ]”. (Price, H. 2001,). The reports available up to date have reserved the combination use of antidepressant-antipsychotics only for psychotic depression, or for treatment-resistant depression.
More recently, with the development of new a typical antipsychotic medications, there have been reports of using an a typical antipsychotic in combination with an antidepressant, such as an SSRI (selective serotonin reuptake inhibitor), to treat a specific subgroup of depressed patients that do not respond to antidepressants alone, that is, patients who have treatment-resistant depression (TRD). See, for example, WO 99/61027, which describes the use of SSRI's and a typical antipsychotics for partially-responding or treatment-resistant depression. Shelton, C. R., et al: 2001; Ostroff, R. B. et al: 1999; Alpert, J. E., et al.: 2002; Parker, G., 2002; Pitchot, W., et al 2001; O'Connor, M. 1998; Kaplan, M. 2000. See also reviews on the combined use of a typical antipsychotics and SSRIs for treatment resistant depression (Thase 2002). Nierenberg (Nierenberg. A. A., 1992) had noted that the cause of treatment-resistant depression may be an unrecognized psychosis, that may explain—at least in part—of why the “treatment-resistant” depression group improved with the addition of an antipsychotic medication.
As used herein, the term “treatment-resistant” is used as that term is understood by one skilled in the art, and as used in the present invention, means a lack of therapeutic response after at least one trial of an antidepressant at an adequate dose for six weeks.
While the newer drugs referred to as a typical antipsychotics have improved side effect profiles as compared with traditional antipsychotics, especially as regards to NMS, TD and acute extrapyramidal symptoms (EPS), they too can produce undesirable side effects, including potentially serious adverse effects not always present with some of the typical (older) antipsychotics. These adverse effects include agranulocytosis, (specifically with clozapine), neutropenia, seizure, weight gain, hyperglycemia, diabetes, diabetic ketoacidosis as a first sign of diabetes, hyperlipidemia/hypercholesterolemia, hyperprolactinamia (with potential consequent bone loss, depressive effect, and sexual dysfunction), orthostatic hypotension, tardive dyskinesia (TD) an involuntary movement, EPS, NMS, in EKG a prolongation of QTC interval with the potential of life threatening arrhythmia (ziprasidone), and other adverse effects (dry mouth, sedation, increase in appetite, asymptomatic elevations in liver enzymes, hypersalivation, tachycardia, hypotension, hypertension, constipation, and urinary incontinence). In addition, there are also some rare side effects associated with the a typical antipsychotics, such as priapism, rabbit syndrome, chorea, eosinophilia, Pisa syndrome, periodic leg movements and restless legs syndrome, and sudden death in patients receiving clozapine. There have also been reports of mania, and withdrawal syndromes.
Therefore, when combining antipsychotics with antidepressants it should be noted that some of their adverse effects may add up, or may present with new risks. These added or new risks may include the increase in weight; risk factor for diabetes, cardiac and other medical morbidity and mortality; hyponatremia, an electrolyte disturbance; TD; akathisia and extrapyramidal symptoms (EPS); and the potentially dangerous serotonin syndrome.
The a typical antipsychotics and dopamine system stabilizers are also expensive drugs. Thus, to date, the use of a typical antipsychotic medications has been restricted to their use in combination with antidepressants, for the treatment of the following subtypes of illness: schizoaffective disorder; psychotic depression; bipolar (manic-depressive) disorder; and treatment-resistant depression. In all of these categories, the use of antipsychotic medication may be expected due to its effects on contributory psychosis, or severe agitation.
There have been no reports recommending that the combination therapy can or should be used for a major depressive disorder, or for other depressions as an initial treatment, upon initial presentation to a health care provider (or as soon as possible), or for using the combination as a treatment of first choice, for reducing the risk of suicide.
Standard therapeutic methods of treating persons suffering from various types of depression, including major depressive disorder, who are at risk for suicide, and in particular those who are at high risk of suicide remain inadequate. There remains a need for an initial form of treatment to reduce the risk of suicide and other pathologies associated with depression, and in particular with major depressive disorder.
Effective methods of treating the symptoms associated with smoking cessation and nicotine withdrawal are similarly lacking. Unfortunately, smoking cessation rates at 1 year are very low, for the nicotine transdermal system (patch) it is 16.4%, for buproprion (Zyban) it is 23-30% (and with their combination is still only 28-35%). The smoking cessation rate is low even with the educational programs by the American Lung Association (19.0%-24.8%) or by the American Cancer Society (12.1-22.4%) (Migaly, P. smoking cessation book in progress). Therefore there is a need for improvement.
Different aspects of smoking cessation and treatment of nicotine withdrawal had been addressed before. U.S. Pat. No. 5,780,051 addresses the issue of antidepressants (including bupropion) with some other criteria; U.S. Pat. No. 6,582,737 addresses the use of bupropion with different criteria. U.S. Pat. No. 5,780,051 addresses the issue of antipsychotics including olanzapine, with some other criteria, and U.S. Pat. No. 6,159,963 also addresses the use of olanzapine in the treatment of nicotine dependence, and for withdrawal syndrome, again together with some other criteria.
None of the prior art has suggested the combination of low dose a typical antipsychotics or dopamine system stabilizers with newer antidepressants for treatment of smoking cessation and nicotine withdrawal, or the need to target cognitive distortions with this combination. However, the combination of these categories of medications are likely to potentiate each other and to provide an increased effectiveness.